8-fluoro-2-{8 3-(4-fluorophenylanilinopropyl{9 -gamma-carboline

ABSTRACT

8-Fluoro-2-(3-(4-fluorophenylanilino)propyl)-1,2,3,4,tetrahydro-5H -pyrido(4,3-b)indole has been found to be a very useful tranquilizer at low dosages when administered to warmblooded animals. The new compound and its non-toxic acid addition salts have an oral ED50 of about 20 mg./kg. and an oral LD50 of 700 mg./kg.

United States Patent Bernstein et al. Aug. 29, 1972 [54]8-FLUORO-2-[3-(4- [56] References Cited F OR PH NYL NIL A i g E jINOPROPYL] UNITED STATES PATENTS 3,382,250 5/1968 Johnson et a1...260/296 A [72] Invenmrs' a? f f f g Eff 3,448,114 6/1969 Johnson etal. ..260/296 A fz a gz i g; 3,466,293 9/1969 Johnson et a1 ..260/2949 9Bluff Primary Examiner-Alan L. Rotman 73 Assignee: Abbott Laboratories,North AtwmeyR9bert Niblack Chicago, Ill. [57] ABS CT [22] Filed: May 3,1971 8-Fluoro-2-[3-(4-fluorophenylan1lmo)propyl]- PP 9,9021,2,3,4,-tetrahydro-5H-pyrido[4,3-b]indole has been found to be a veryuseful tranquilizer at low dosages when administered to warm-bloodedanimals. The new [52] US. Cl ..260/296 A, 260/295 S, compound and itsnomtoxic acid addition salts have Int Cl Com 31/42 an oral ED of about20mg./kg. and an oral LD of [58] Field of Search ..260/295 s, 296 A 7002 Claims, N0 Drawings 8-FLUORO-2-[3-(4-FLUOROPHENYLANILINOPROPYL]-GAMMA- CARBOLINE DETAILED DESCRIPTION OF THEINVENTION hydrochloride with N-( 3-halopropyl)-p-fluoroaniline in thepresence of an acid acceptor in a suitable solvent. The reaction mixturediluted with water can be extracted with a suitable water-immisciblesolvent in which the new compound is soluble. The free base so obtainedcan be converted to suitable salts by standard methods and, if desired,the conversion to a suitable salt may be used for the purification ofthe free base that can be obtained from the salt.

As illustrated but without intent to limit the present invention,reference is made to the following detailed example:

EXAMPLE A mixture of 4.05 g. of 8-fluoro--y-carboline hydrochloride,4.4g. of N-(3-bromopropyl)-pfiuoroaniline, 5 g. of anhydrous potassiumcarbonate and 3g. of potassium iodide was heated and stirred in 50 ml.of dimethylformamide at 80 C. for 7 hours. The reaction mixture wassubsequently cooled and poured into water and extracted therefrom withchloroform and the chloroform extract was washed with water, dried overmagnesium sulfate and evaporated to dryness. The crude product wasconverted to the dihydrochloride and the obtained slat wasrecrystallized from ethanol to produce 4.7 g. (65 percent of theory) of8-fluoro-2-[3-(4-fluorophenylanilino)propyll-y-carboline dihydrochloridemelting at l78-l82 C. For analytical purposes, the dipicrate salt wasprepared from the free base and picric acid in aqueous solution at pH 1.This salt melts at l39-l42 C.

The above compound was tested in mice by the method published byPsychopharmacology by the U.S. Public Health Service (Publication No.1836 of 1968, Section 11 on Psychiatric Agents). In this test, theanimals were given a 1% wt./vol. suspension of the compound in 0.3%wt./vol. tragacanth by gavage. The animals were subcutaneouslyadministered at the same time a 1.0% aqueous solution of methamphetaminehydrochloride at a dose of 3 mgJkg. The animals were then placed inmotor activity chambers equipped with photocells which were connected tocounting devices with three animals per chamber and three chambers perdose level. In each instance, a control group of three animals receivingno test drug was also tested. At a dose of 5 mg./kg., the test showed areduction of ii3ff8i35$hfiifi lrgbficlllii r e fiilfii were 30 percent,46 percent and 73 percent, respectively. By administering the abovecompound intraperitoneally at a dose 50 mg./kg., activity of the animalswas reduced by 97 percent over the control group.

Although the above example shows the activity only for thedihydrochloride salt, similar results are obtained when the free base isused per se or when converted to other non-toxic acid addition saltssuch as the sulfate, phosphate, acetate, tartrate, citrate or succinate.

We claim:

1. 8-Fluoro-2-[3-(4-fluorophenylanilino)propyl]-l,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole or a nontoxic acid additionsalt thereof.

2. 8-Fluoro-2-[3-(4-fluorophenylanilino)propyl]-l,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole dihydrochloride.

Patent No. 3,687,961 Dated Au gust29, 1972 Edith Bernstein, David LvonGarmaise and Nicholas I Peter Plotnikoff It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Inventor(s) In the title; abstract, line 1; Column 1, line 5; Column 1;line a; Colman 2, line 4; Claim 1, line 37; and Claim I 2, line 4-0;blease delete "(4-fluorophenylanilino)" and substitute therefor: "(h-fluoropheriylamino)" Signed and sealed this 14th day of January 1975.

(SEAL) Attest:

McCOY M. GIBSON JR. Attesting Officer c MARSHALL DANN Commissioner ofPatents Uscomm-oc scan-p:

FORM PO-IOSO (10-69) i 0.5. aovmuunm murmur. emu: nu o-aea-1

2. 8-Fluoro-2-(3-(4-fluorophenylanilino)propyl)-1,2,3,4-tetrahydro-5H-pyrido(4,3-b)indole dihydrochloride.